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In this report, we describe the clinical and immunologic consequences of a novel FOXP3 variant in an infant with refractory IPEX syndrome. Rapid whole-genome sequencing revealed a missense variant c.1050C&amp;gt;G (p.Ile350Met) in the forkhead domain of FOXP3. FOXP3 expression was abrogated in the regulatory T cell (Treg) subset but was maintained at low levels in activated effector T cells. The frequency of Treg-specific demethylated region (TSDR)\u2013demethylated T cells was within normal range at birth, but it increased to pathologically high levels at 2 wk of age, prior to manifestation of disease symptoms. These results support the clinical relevance of the TSDR-demethylated cell percentage in evaluation of disease activity in IPEX. This case highlights a severe form of IPEX syndrome refractory to multiple immunosuppressive agents and the importance of early immunological studies to verify the clinical significance of novel genetic findings.<\/jats:p>","DOI":"10.70962\/jhi.20250249","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T13:10:36Z","timestamp":1774617036000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Refractory infantile IPEX with Treg-restricted FOXP3null expression caused by a novel variant in\n                    <i>FOXP3<\/i>"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6352-9740","authenticated-orcid":true,"given":"Ahmad","family":"Rayes","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/053hkmn05","id-type":"ROR","asserted-by":"publisher"}],"name":"Pediatric Immunology and Hematopoietic Cell Transplantation\/Cellular Therapy Program, Primary Children\u2019s Hospital, University of Utah 1 , Salt Lake City, UT,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8727-2046","authenticated-orcid":true,"given":"Akshaya","family":"Ramachandran","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00f54p054","id-type":"ROR","asserted-by":"publisher"}],"name":"Stanford University 2 Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, , Stanford, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3030-8420","authenticated-orcid":true,"given":"Michael A.","family":"Pulsipher","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/053hkmn05","id-type":"ROR","asserted-by":"publisher"}],"name":"Pediatric Immunology and Hematopoietic Cell Transplantation\/Cellular Therapy Program, Primary Children\u2019s Hospital, University of Utah 1 , Salt Lake City, UT,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03r0ha626","id-type":"ROR","asserted-by":"publisher"}],"name":"Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at the University of Utah 3 , Salt Lake City, UT,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4431-7515","authenticated-orcid":true,"given":"J. 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